Process for preparing substituted 1,2,4-triazole derivatives

ABSTRACT

New 1-alkyl-3,5-disubstituted-1,2,4-triazole derivatives of following formula I ##STR1## wherein R may represent phenyl; phenyl substituted by a radical selected from (C 1-4 )alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec.-butyl, isobutyl or tert.-butyl, (C 1-4 )alkoxy, e.g. methoxy, ethoxy, propoxy, butoxy, isobutyloxy or tert.-butoxy, fluoro, chloro, bromo, nitro, amino, cyano, carbamoyl, carboxy, hydroxymethyl, methylenedioxy and trifluoromethyl; dichlorophenyl; dimethoxyphenyl; 3,4,5-trimethoxyphenyl; 
     R 1  may represent phenyl, phenyl substituted by a radical selected from (C 1-4 )alkyl as above defined, (C 1-4 )alkoxy as above defined, fluoro, chloro, bromo, hydroxymethyl, (C 2-4 )aliphatic acyloxymethyl, e.g. acetoxymethyl, propionyloxymethyl or butyryloxymethyl, carbamoyloxymethyl, bromomethyl and dimethylaminomethyl; dimethylphenyl; dimethoxyphenyl; phenyl contemporaneously substituted by o-hydroxymethyl and chloro; 
     R 2  represents a (C 1-4 )alkyl group as above defined; with the proviso that R and R 1  cannot simultaneously represent phenyl; 
     With the further proviso that, when R is phenyl, R 1  cannot be p-chlorophenyl; and processes for their preparation. 
     The compound of the invention have CNS depressant utility. They are especially useful as sedatives and hypnotics. Some of the compounds of the invention are also useful as anxiety relieving means.

CROSS REFERENCE TO RELATED APPLICATION

This is a division, of application Ser. No. 720,479 filed 9/3/78*, nowU.S. Pat. 4,119,635. *which in turn is a continuation-in-part ofapplication Ser. No. 272,105, Filed July 17, 1972, now abandoned.

SUMMARY OF THE INVENTION

This invention relates to new 1-alkyl-3,5-disubstituted-1,2,4-triazolederivatives of following formula I and to processes for theirmanufacture: ##STR2## wherein R may represent phenyl; phenyl substitutedby a radical selected from (C₁₋₄) alkyl, e.g. methyl, ethyl, propyl,isopropyl, butyl, sec.butyl, isobutyl or tert.-butyl, (C₁₋₄)alkoxy, e.g.methoxy, ethoxy, propoxy, butoxy, isobutyloxy or tert.-butoxy, fluoro,chloro, bromo, nitro, amino, cyano, carbamoyl, carboxy, hydroxymethyl,methylenedioxy and trifluoromethyl; dichlorophenyl, dimethoxyphenyl;3,4,5-trimethoxyphenyl;

R₁ may represent phenyl; phenyl substituted by a radical selected from(C₁₋₄)alkyl as above defined, (C₁₋₄)alkoxy as above defined, fluoro,chloro, bromo, hydroxymethyl, (C₂₋₄)aliphatic acyloxy-methyl, e.g.acetoxymethyl, propionyloxymethyl or butyryloxymethyl,carbamoyloxymethyl, bromomethyl and dimethylaminomethyl; dimethylphenyl;dimethoxyphenyl; phenyl contemporaneously substituted by o-hydroxymethyland chloro;

R₂ represents a (C₁₋₄)alkyl group as above defined; with the provisothat R and R₁ cannot simultaneously represent phenyl; with the furtherproviso that, when R is phenyl, R₁ cannot be p-chlorophenyl.

The compounds of the invention have CNS depressant utility. They areespecially useful as sedative and hypnotics. Some of the compounds ofthe invention are also useful as anxiety relieving means.

A preferred group of compounds comprises those compounds of formula Iwherein R and R₂ are defined as above and R₁ is the radical ##STR3##wherein R₃ may represent hydrogen or hydroxy.

A most preferred group of compounds comprises those compounds of formulaI wherein R represents phenyl; phenyl substituted by a radical selectedfrom methyl, methoxy, fluoro, chloro, nitro and methylenedioxy;dichlorophenyl; dimethoxyphenyl or 3,4,5-trimethoxyphenyl;

R₁ is the radical ##STR4## wherein R₃ is hydroxy, and R₂ stands for amethyl group. A second most preferred group of compounds comprises thosecompounds of formula I wherein R represents phenyl; phenyl substitutedby a radical selected from methyl, methoxy, trifluoromethyl,methylenedioxy, chloro and amino; dimethoxyphenyl or3,4,5-trimethoxyphenyl,

R₁ is the radical ##STR5## wherein R₃ represents hydrogen and R₂ standsfor a methyl radical.

A general method for preparing the 1,2,4-triazoles of this inventioncomprises either reacting a compound of formula ##STR6## with a compoundof formula

    R.sub.1 -CX                                                III

or reacting a compound of formula ##STR7## with a compound of formula

    R--CX                                                      V

in the above formulas II thru V the radicals R, R₁ and R₂ have thepreviously indicated meanings, CX is a functional group selected fromcarboxy, dithiocarboxy, carbonyl halide, carboxy anhydride, orthoester,imidate, thioimidate, imidoyl halide, amidino and cyano, Y is NH, and,when a compound R-CX is employed wherein the group CX contains anitrogen atom, it represents oxygen or sulfur.

The process essentially consists in a condensation reaction, duringwhich, depending on the nature of the reacting groups CX and Y, water,hydrogen sulfide, hydrogen halide, ammonia, alkanols, carboxylic acidsor mixtures thereof are formed as by-products. The reaction isillustrated by the following scheme: ##STR8## A tipical method forcarrying out the condensation reaction involves heating the pair ofreagents of formulas II and III or IV and V in the absence of solvent ata temperature of from about 80° to about 150° C. for several hours. Anexcess of the compound R₁ CX or R--CX may be advantageously employed tospeed up the reaction. In those instances where the two components cannot be melted without decomposition, a high boiling inert organicsolvent may be used, such, for instance, xylene, halogenated aromatichydrocarbons, N,N-dimethylformamide and the like. Catalytic amounts ofacids such as p-toluenesulfonic acid or hydrogen halides, as well asimidate or amidine acid salts may be advantageously added to speed upthe cyclization rate.

The foregoing cyclization reaction may also be effected in two stepswhen the group CX in the compounds of formulas III and V corresponds toan acyl halide. Thus, for instance, a molecular amount of3-chlorobenzimidic acid 2-methylhydrazide, i.e., the compound of formula(II) wherein R is 3- chlorophenyl, R₂ is methyl and Y is NH, is stirredfor 15-25 hours at room temperature in an halogenated lower hydrocarbonsolution and in the presence of an excess over the equimolecularproportion of a tertiary organic base, with a molecular amount of2,6-dimethoxybenzoyl chloride, i.e., the compound of formula (III)wherein R₁ is 2,6-dimethoxyphenyl and CX corresponds to carbonylchloride. After washing with aqueous NaHCO₃ and evaporating the solvent,the intermediate 2-methyl-2-(2,6-dimethoxybenzoyl)hydrazine of3-chlorobenzimidic acid is obtained. This latter compound is cyclized byheating in an inert organic solvent at a temperature from about 80° toabout 150° C. for several hours. A catalytic amount of a base such as analkali metal hydroxide or an alkali metal alkoxide preferably sodiummethoxide or ethoxide, may be used to improve the reaction rate. In somecase, the obtained 1,2,4-triazole can be further transformed bygenerally known chemical reactions into another derivative which isencompassed by the general formula (I). As an example, the phenylradicals R and R₁ may be chemically modified by introducing newsubstituents or by transforming a pre-existing substituent into adifferent functional group. If a triazole of formula I is desiredwherein R₁ represents phenyl substituted by an o-hydroxymethyl groups,or phenyl contemporaneously substituted by o-hydroxymethyl and chloro, afurther suitable method for preparing the inventive compounds involves anovel rearrangement of the hydrazones of 4-hydrazino-1H-2,3-benzoxazinesof formula VI, as indicated by the following scheme: ##STR9## wherein Rand R₂ are as above defined and R₅ is hydrogen or chloro.

It is quite apparent that, in this case, further chemicaltransformations of the obtained compounds are possible. In particular,the o-hydroxymethyl group may be transformed by known chemicalprocedures such as, for instance, hydrogenation, substitution, acylationand the like, into another functional group such as methyl, bromomethyl,dimethylaminomethyl, (C₂₋₄)aliphatic acyloxy-methyl orcarbamoyloxymethyl. According to the novel rearrangement process,hydrazones of benzaldehyde or substituted benzaldehydes with4-hydrazino-1H-2,3-benzoxazines, when heated in an organic solvent whichis advantageously selected from lower alkanols in the presence of anacidic catalyst, such as for instance, hydrogen chloride or p-toluenesulfonic acid, rearrange to 1,2,4-triazoles.

The final compounds are easily recovered by filtration or by evaporationof the solvent. The starting hydrazones are prepared according to theprocedure described in British Pat. No. 1,227,490. The hydrazones whichundergo the rearrangement may also be used in a crude state without anyparticular purification.

As stated before, the compounds of the invention have CNS depressantutility. More exactly, the compounds of Examples 1,2,3,5-10, 14, 31(42),32(56), 34, 35 and 45(55) are useful as sedatives and hypnotics. Thesepharmacological properties were ascertained by following the operativescheme and the manipulation procedure described by S. Irwin inPsychopharmacologia (Berl.), 13, 222, 1968. Especially, there werestudied the biological effects of the compounds on two of the parameterswhich are closely related to the above properties, namely the"spontaneous activity" and the "righting reflex". The effects of thecompounds on these two parameters were expressed as ED₅₀ values ie., theamount of compound tested which reduces the spontaneous activity andrighting reflux scores of test animals to 50% of those of the controls.The scores are the same as those reported by S. Irwin in the citedpaper. For each compound it was also determined the minimal dosis whichproduces complete hypnosis of the test animals (MHD).

The obtained results are summarized in the following table, which alsoreports the toxicities of the tested substances, expressed as LD₅₀values. For comparison purposes, also the activity of two knowncompounds was determined, The known compounds are1-methyl-3,5-diphenyl-1,2,4-triazole (Compound A, Atkinson et al. Journ.Chem. Soc., 1954, 141, 1954) and1-methyl-3-phenyl-5-(p-chlorophenyl)-1,2,4-triazole (Compound B, Huisgenet al., Journ. Org. Chem., 24, 892, 1959).

    __________________________________________________________________________           Decrease of spontaneous                                                                   Impairment of                                                                             Minimal hypnotic                                                                       Toxicity                              Compound of                                                                          activity    righting reflex                                                                           dosis    LD.sub.50                             Example                                                                              ED.sub.50 mg/kg i.p.(mice)                                                                ED.sub.50 mg/kg i.p.(mice)                                                                mg/kg i.p. (mice)                                                                      mg/kg i.p.(mice)                      __________________________________________________________________________    1      60          100         300      1000                                  2      60          60          300      500                                   3      30          10          200      500                                   5      30          50          150      400                                   6      50          25          600      1000                                  7      30          20          80       500                                   8      80          100         600      >1000                                 9      60          60          300      1000                                  10     60          40          300      1000                                  14     80          80          300      >1000                                    31(42)                                                                            60          50          300      >1000                                    32(56)                                                                            30          20          200      >1000                                 34     30          20          60       200                                   35     60          50          300      1000                                     45(55)                                                                            30          50          300      700                                   A      >100        300         >1000    1000                                  B      >300        >300        >600     >1000                                 __________________________________________________________________________

The compounds of Examples 34 and 45(55) are also useful as anxietyrelieving means. This property was investigated on the basis of thesecondary response avoidance test, which was performed as described byG. Maffii, Journ. Pharm. Pharmacol., 11, 192, 1959. It has been foundthat the compounds of Examples 34 and 45(55) display a remarkableantianxiety effect in rats at a dose of 20 mg/kg i.p.

While the preferred routes of administration of these compounds are bymouth or parenterally, other routes may be useful employed. For oraladministration the substances are embodied in pharmaceutical dosageforms such as tablets, capsules, elixirs, solution and the like. Thedosage unit may contain the usual excipients such as, for example,starch, gums, alcohols, sugars, fatty acids, etc. For parenteraladministration, the compounds are administered in the form of aqueoussolution, admixed with conventional antioxidant, preservative, chelatingand buffering agents such as, for examples, sodium formaldehydesulfoxylate, benzyl alcohol, ethylenediaminetetraacetic acidderivatives, sodium acetate, etc. The daily dosage range is from about 1to about 50 mg/kg of body weight, preferably administered in divideddoses.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The following non-limitative examples describe in detail representativecompounds of this invention and methods for their preparation.

EXAMPLE 1: 5-(2-Hydroxymethylphenyl)-1-methyl-3-phenyl-1,2,4-triazole

A suspension of 1.2 g. of4-(2-benzylidene-1-methylhydrazino)-1H-2,3-benzoxazine in 12 ml. ofethanol and 12 ml. of aqueous 5% HCl is heated on a water bath for threehours. The ethanol is removed by distillation and the residue,neutralized with aqueous NaHCO₃, is cooled to about 0° C. Theprecipitate is filtered and crystallized from ethanol. M.p. 122° C.Yield 96%.

EXAMPLES 2-17:

Pursuant to the method described in Example 1, the following compoundsare prepared:

    __________________________________________________________________________     ##STR10##                                                                    No. of                      M.p. ° C.                                  Example                                                                              R          R.sub.1                                                                              R.sub.2                                                                          B.p. ° C.                                                                   Starting Compound                                  ##STR11##                                                                                ##STR12##                                                                             CH.sub.3                                                                         84-85                                                                              4-[2-(2-chlorobenzylidene)-1-methylhydraz                                     ino]- 1H-2,3-benzoxazine                     3                                                                                   ##STR13##                                                                                ##STR14##                                                                             CH.sub.3                                                                         91-92                                                                              4-[2-(3-chlorobenzylidene)-1-methylhydraz                                     ino]- 1H-2,3-benzoxazine                     4                                                                                   ##STR15##                                                                                ##STR16##                                                                             CH.sub.3                                                                         127-128                                                                            4-[2-(4-chlorobenzylidene)-1-methylhydraz                                     ino]- 1H-2,3-benzoxazine                     5                                                                                   ##STR17##                                                                                ##STR18##                                                                             CH.sub.3                                                                         95-97                                                                              4-[2-(3-fluorobenzylidene)-1-methylhydraz                                     ino] - 1H-2,3-benzoxazine                    6                                                                                   ##STR19##                                                                                ##STR20##                                                                             CH.sub.3                                                                         125-126                                                                            4-[2-(2-methylbenzylidene)-1-methylhydraz                                     ino]- 1H-2,3-benzoxazine                     7                                                                                   ##STR21##                                                                                ##STR22##                                                                             CH.sub.3                                                                         105-106                                                                            4-[2-(3-methylbenzylidene)-1-methylhydraz                                     ino]- 1H-2,3-benzoxazine                     8                                                                                   ##STR23##                                                                                ##STR24##                                                                             CH.sub.3                                                                         157-158                                                                            4-[2-(2-methylbenzylidene)-1-methylhydraz                                     ino]- 1H-2,3-benzoxazine                     9                                                                                   ##STR25##                                                                                ##STR26##                                                                             CH.sub.3                                                                         110-112                                                                            4-[2-(3-methoxybenzylidene)-1-methylhydra                                     zino]- 1H-2,3-benzoxazine                    10                                                                                  ##STR27##                                                                                ##STR28##                                                                             CH.sub.3                                                                         162-163                                                                            4-[2-(3-nitrobenzylidene)-1-methylhydrazi                                     no]- 1H-2,3-benzoxazine                      11                                                                                  ##STR29##                                                                                ##STR30##                                                                             CH.sub.3                                                                         175-176                                                                            4-[ 2-(4-nitrobenzylidene)-1-methylhydraz                                     ino]- 1H-2,3-benzoxazine                     12                                                                                  ##STR31##                                                                                ##STR32##                                                                             CH.sub.3                                                                         118-119                                                                            4-[2-(3,4-dichlorobenzylidene)-1-methylhy                                     drazino]- 1H-2,3-benzoxazine                 13                                                                                  ##STR33##                                                                                ##STR34##                                                                             CH.sub.3                                                                         150-151                                                                            4-[2-(3,5-dimethoxybenzylidene)-1-methylh                                     ydrazino]- 1H-2,3-benzoxazine                14                                                                                  ##STR35##                                                                                ##STR36##                                                                             CH.sub.3                                                                         122-123                                                                            4-[2-(3,4-methylenedioxybenzylidene)-1-me                                     thylhydrazino]- 1H-2,3-benzoxazine           15                                                                                  ##STR37##                                                                                ##STR38##                                                                             CH.sub.3                                                                         174-176                                                                            4-[2-(3,4,5-trimethoxybenzylidene)-1-meth                                     ylhydrazino]- 1H-2,3-benzoxazine             16                                                                                  ##STR39##                                                                                ##STR40##                                                                             CH.sub.3                                                                         131-132                                                                             4-(2-benzylidene)-1-methylhydrazino]-                                        6-chloro-1H-2,3-benzoxazine                  17                                                                                  ##STR41##                                                                                ##STR42##                                                                             CH.sub.3                                                                         209-210                                                                            4-[2-(4-nitrobenzylidene)-1-methylhydrazi                                     no]- 6-chloro-1H-2,3-benzoxazine             __________________________________________________________________________

EXAMPLE 18:5-(2-Acetoxymethylphenyl)-1-methyl-3-(4-nitrophenyl)-1,2,4-triazole

0.5 Grams of5-(2-hydroxymethylphenyl)-1-methyl-3-(4-nitrophenyl)-1,2,4-triazole areheated on a steam bath for 3 hours with 5 ml. of acetic anhydride andthe residue obtained after evaporation to dryness is crystallized from20 ml. of ethanol. Yield 88%. M.p. 126°-127° C.

EXAMPLE 19:5-(2-Carbamyloxymethylphenyl)-1-methyl-3-(o-tolyl)-1,2,4-triazole

Dry halogen chloride is bubbled for 30 minutes at about 0°-5° C. into asuspension of 2.8 g. of1-methyl-3-(o-tolyl)-5-(2-hydroxymethylphenyl)-1,2,4-triazole and 1.82g. of sodium cyanate in 50 ml. of chloroform. After standing for 15minutes at room temperature, the solution is evaporated and the residuedissolved in diethyl ether. After washing the ether solution withaqueous sodium bicarbonate and drying over Na₂ SO₄, the solvent isevaporated and the crude product is crystallized from benzene. M.p.126°-128° C. Yield 68%.

EXAMPLES 20-24:

According to the procedure described in Example 19, the followingcompounds are prepared:

    __________________________________________________________________________     ##STR43##                                                                    No. of                        M.p. ° C.                                                                   Starting Material                          Example                                                                              R         R.sub.1   R.sub.2                                                                          B.p. ° C.                                                                   5-(2-hydroxymethylphenyl)-1,2,4-triazol                                       e                                          __________________________________________________________________________    20                                                                                  ##STR44##                                                                               ##STR45##  CH.sub.3                                                                         188-189                                                                            1-methyl-3-(m-tolyl)-                      21                                                                                  ##STR46##                                                                               ##STR47##  CH.sub.3                                                                         182-183                                                                            1-methyl-3-(p-tolyl)-                      22                                                                                  ##STR48##                                                                               ##STR49##  CH.sub.3                                                                         149-150                                                                            1-methyl-3-(2-chlorophenyl)-               23                                                                                  ##STR50##                                                                               ##STR51##  CH.sub.3                                                                         192-193                                                                            1-methyl-3-(3-chlorophenyl)-               24                                                                                  ##STR52##                                                                               ##STR53##  CH.sub.3                                                                         173-174                                                                            1-methyl-3-(4-chlorophenyl)-               __________________________________________________________________________

EXAMPLE 25: 1-Methyl-3-phenyl-5-(2-bromomethylphenyl)-1,2,4-triazole

To 300 ml. of dichloromethane saturated with dry hydrogen bromide 7 g.of 1-methyl-3-phenyl-5-(2-hydroxymethylphenyl)-1,2,4-triazole are added.The solution is allowed to stand at room temperature for a night andafter washing with aqueous sodium bicarbonate and then with water it isdried over sodium sulfate. Evaporation of the solvent andcrystallization from hexane afford the title compound. M.p. 83°-85° C.Yield 84%.

EXAMPLES 26-28:

By operating as in Example 25, the following compounds are preparedstarting from their corresponding 2-hydroxymethyl derivatives:

(26) 5-(2-bromomethylphenyl)-1-methyl-3-(m-tolyl)-1,2,4-triazole. M.p.116°-117° C. Yield 85%.

(27) 5-(2-bromomethylphenyl)-1-methyl-3-(3-chlorophenyl)-1,2,4-triazole.M.p. 126°-128° C. Yield 71%.

(28) 5-(2-bromomethylphenyl)-1-methyl-3-(4-nitrophenyl)-1,2,4-triazole.M.p. 285° C. Yield 42%.

EXAMPLE 29: 1-Methyl-3,5-bis(o-tolyl)-1,2,4-triazole

2.81 Grams of1-methyl-3-(o-tolyl)-5-(2-hydroxymethylphenyl)-1,2,4-triazole and 0.365g. of dry hydrogen chloride in 100 ml. of ethanol are hydrogenated inthe presence of 1 g. of 10% palladiated charcoal as a catalyst.

After taking up of one molecular amount of hydrogen, the catalyst isfiltered off and the filtrate evaporated to dryness. The residue istaken up with a NaHCO₃ solution and extracted with diethyl ether; afterdrying and evaporation of the solvent, the title compound is distilledat 170° C./0.08 mm Hg. Yield 76%.

EXAMPLES 30-38:

Pursuant to the procedure described in Example 29 and starting fromtheir corresponding 2-hydroxymethylphenyl compounds, the followingderivatives are prepared:

(30) 1-Methyl-3-(o-tolyl)-5-phenyl-1,2,4-triazole. B.p. 170° C./0.1 mmHg. Yield 80%.

(31) 1-Methyl-5-(o-tolyl)-3-phenyl-1,2,4-triazole, B.p. 160° C./0.1 mmHg. Yield 76%.

(32) 1-Methyl-3-(m-tolyl)-5-(o-tolyl)-1,2,4-triazole. M.p. 80°-81° C.Yield 86%.

(33) 1-Methyl-3-(p-tolyl)-5-(o-tolyl)-1,2,4-triazole. M.p. 139°-140° C.Yield 78%.

(34) 1-Methyl-3-(3-aminophenyl)-5-(o-tolyl)-1,2,4-triazole. M.p.128°-130° C. Yield 51%. In this case the compound is prepared by usingas a starting material1-methyl-3-(3-nitrophenyl)-5-(2-hydroxymethylphenyl)-1,2,4-triazole andhydrogenating in a single step the nitro and the hydroxymethyl group.

(35) 1-Methyl-3-(3-methoxyphenyl)-5-(o-tolyl)-1,2,4-triazole B.p. 190°C./0.03 mm Hg. Yield 79%.

(36) 1-Methyl-3-(3,5-dimethoxyphenyl)-5-(o-tolyl)-1,2,4-triazole. M.p.104°-105° C. Yield 72%.

(37) 1-Methyl-3-(3,4-methylenedioxyphenyl)-5-(o-tolyl)-1,2,4-triazole.M.p. 96°-97° C. Yield 63%.

(38) 1-Methyl-3-(3,4,5-trimethoxyphenyl)-5-(o-tolyl)-1,2,4-triazole.M.p. 175°-176° C. Yield 70%.

EXAMPLE 39:1-Methyl-5-(2-dimethylaminomethylphenyl)-3-(3-chlorophenyl)-1,2,4-triazole.

To a solution of 4. g. of1-methyl-3-(3-chlorophenyl)-5-(2-bromomethylphenyl)-1,2,4-triazole in 50ml. of anhydrous benzene, 8.8 ml. of a benzene solution containing 20%of dimethylamine are added maintaining the temperature of about 5°-10°C. The mixture was maintained under stirring for 16 hours and thenwashed with 10% sodium hydroxide and with an aqueous solution of sodiumchloride. The organic solution is dried over sodium sulfate and thenevaporated. The crude product is purified by distillation at 175°C./0.07 mm Hg. Yield 86%.

EXAMPLE 40-41:

The following compounds are prepared according to the method describedin Example 39 by employing their corresponding 2-bromomethylphenylderivatives as the starting materials:

(40) 1-methyl-5-(2-dimethylaminomethylphenyl)-3-phenyl-1,2,4-triazole.B.p. 180° C./0.07 mm Hg. Yield 96%.

(41)1-methyl-5-(2-dimethylaminomethylphenyl)-3-(m-tolyl)-1,2,4-triazole.B.p. 180° C./0.01 mm Hg. Yield 95%.

EXAMPLE 42:

1-Methyl-5-(o-tolyl)-3-phenyl-1,2,4-triazole

A mixture of 0.56 g. of benzimidic acid 2-methylhydrazide hydrochlorideand 3.8 g. of o-toluic acid chloride is heated under stirring at about120° C. After cooling and addition of diethyl ether, the hydrochlorideof the triazole is collected on filter and then suspended in a sodiumbicarbonate aqueous solution. The free base is extracted with diethylether and the organic phase, after drying over sodium sulfate, isevaporated. The crude compound is purified by distillation at 160°C./0.1 mm Hg. Yield 76%.

EXAMPLES 43-53:

The following triazoles are prepared in accordance with the methoddescribed in Example 42 by using the corresponding acid chlorides andbenzimidic acid hydrazides:

    __________________________________________________________________________    Example              B.p.:° C./mm Hg                                   No.  1,2,4-Triazole  M.p.:° C.                                                                       Acid chloride                                                                          2-Methylhydrazide                      __________________________________________________________________________                                           of                                     43   1-methyl-3-(o-tolyl)-5-phenyl-                                                                170/0.1  benzoic  o-tolumidic acid                       44   1-methyl-3-(3-trifluoromethyl)-                                               5-(o-tolyl)-    87-88    o-toluic 3-trifluoromethylbenzimidic acid       45   1-methyl-3-(3-chlorophenyl)-5-                                                (o-tolyl)       75-76    o-toluic 3-chlorobenzimidic acid                46   1-methyl-5-(2,4-dimethylphenyl)-                                                              105-106  2,4-dimethylben-                                                                       m-toluimidic acid                           3-(m-tolyl)              zoic                                            47   1-methyl-3,5-bis(m-tolyl)                                                                     72-73    m-toluic m-toluimidic acid                      48   1-methyl-3-(3-chlorophenyl)-5-                                                                47-48    2,2-dimethylben-                                     (2,4-dimethylphenyl)-    zoic     3-chlorobenzimidic acid                49   1-methyl-3,5-bis(3-chlorophenyl)-                                                             88-89    3-chlorobenzoic                                                                        3-chlorobenzimidie acid                50   1-methyl-3-(o-tolyl)-5-m-to-                                                  lyl)-           170/0.02 m-toluic o-toluimidie acid                           lyl)-                                                                    51   1-methyl-3-(o-tolyl)-5-p-to-                                                                           p-toluic o-toluimidic acid                           lyl)-                                                                    52   1-methyl-3-(o-tolyl)-5-(p-chloro-                                             phenyl)-        76-78    p-chlorobenzoic                                                                        o-toluimidic acid                      53   1-methyl-3-(o-tolyl)-5-(o-chloro-                                                                      o-chlorobenzoic                                                                        o-toluimidic                                phenyl)-                                                                 __________________________________________________________________________

The benzimidic acid hydrazides employed as the starting materials forpreceding Examples 42-53 are prepared according to the method describedby N. R. Atkinson in J. Chem. Soc. 3319 (1954). The following were soprepared:

o-toluimidie acid 2-methylhydrazine hydrochloride M.p. 85°-88° C. withdecomposition

m-trifluoromethylbenzimidic acid 2-methylhydrazide M.p. 57°-61° C.

m-chlorobenzimidic acid 2-methylhydrazide M.p. 110°-112° C.

m-toluimidic acid 2-methylhydrazide M.p. 79°-81° C.

EXAMPLE 54: 1-Methyl-3-(o-tolyl)-5-phenyl-1,2,4-triazole

A mixture of 1.14 g. of o-toluimidic acid ethyl ester, 1.14 g. of1-methyl-1-benzoylhydrazine and 0.1 g. of o-toluimidic acid esterhydrochloride, as a catalyst, is heated at about 100° C. for three hoursunder reduced pressure (about 200 mm Hg) and then at about 120° C. forfive hours. The raw material is taken up with diethyl ether and theorganic solution is washed with aqueous sodium bicarbonate and thendried over Na₂ SO₄. After evaporation of the solvent, the product isdistilled at 170° C./0.1 mm Hg. Yield 32%.

EXAMPLE 55: 1-Methyl-3-(3-chlorophenyl)-5-(o-tolyl)-1,2,4-triazole

A mixture of 6.85 g. of 1-methyl-1-(o-toluyl)-hydrazine, 13.8 g. ofm-chlorobenzimidic acid ethyl ester and 1.8 g. of the hydrochloride ofm-chlorobenzimidic acid ethyl ester is heated with stirring under vacuumfor 18 hours and simultaneously ethanol and m-chlorobenzonitrile aredistilled off. Then, maintaining the temperature at about 65° C., 40 ml.of ethanol are added followed by a sodium ethylate solution preparedfrom 0.336 g. of sodium and 20 ml. of ethanol. The mixture is refluxedfor 6 hours and after standing over night, the insoluble precipitate isfiltered off. The filtrate is evaporated to dryness. The residue isdissolved in 100 ml. of diethyl ether and after washing the organiclayer successively with aqueous 5% Na₂ CO₃, 5% HCl and water, thesolution is dried over sodium sulfate. The crude product obtained byevaporation of the diethyl ether solution is crystallized from ethanol.Yield 66%. M.p. 77°-78° C.

EXAMPLES 56-57:

By following the procedure of Example 55, the following triazoles areprepared:

(56) 1-methyl-3-(m-tolyl)-5(o-tolyl)-1,2,4-triazole. M.p. 80°-81° C., byreacting 1-methyl-1-(o-toluyl)hydrazine with m-toluimidic acid ethylester and its corresponding hydrochloride as a catalyst.

(57) 1-methyl-5-(3-chlorophenyl)-3-(o-tolyl)-1,2,4-triazole

M.p. 86°-88° C., by reacting 1-methyl-1-(3-chlorobenzoyl)-hydrazine withtoluimidic acid ethyl ester and its corresponding hydrochloride as acatalyst.

EXAMPLE 58:1-Methyl-3-(3-chlorophenyl)-5-(2,6-dimethoxyphenyl)-1,2,4-triazole

To a solution of 5.08 g. of 3-chlorobenzimidic acid 2-methyl-hydrazideand 4.3 ml. of triethylamine in 85 ml. of dichloromethane, 5.6 g. of2,6-dimethoxybenzoyl chloride in 50 ml. of dichloromethane are addedunder stirring. The agitation is continued for about 20 hours. Thesolution is then washed with diluted sodium bicarbonate and with waterand dried over Na₂ SO₄. The solvent is evaporated and the productcrystallized from 1,2-dimethoxyethane. M.p. 172°-173° C. Three grams ofthe so obtained1-methyl-1-(2,6-dimethoxybenzoyl)-2-(3-chlorobenzimidoyl)-hydrazine isadded to a solution of 0.06 g. of sodium in 37 ml. of n-pentanol and themixture is heated at 150° C. for 6 hours. The solvent is then distilledoff and the crude product, after treatment with water, is collected on afilter. Crystallization from diisopropyl ether affords a product whichmelts at 147°-148° C. Overall yield 47%. This compound has been preparedalso through a one-step process according to the method described inExample 54 by reacting 3-chlorobenzimidic acid ethyl ester with1-methyl-1-(2,6-dimethoxybenzoyl)hydrazine. The starting imidates ofExamples 55 to 57 and the corresponding salts are prepared according toliterature methods. (Pinner, "Die Imidoaether und Ihre Derivate" - R.Oppenheim, Berlin, 1892; L. Weintraub et al., J. Org. Chem., Vol. 33,No. 4, page 1679, 1968). The starting 1-methyl-1-benzoylhydrazines areprepared according to the method described by A. R. MacCarthy et al. InJ.C.S.(B) 1185 (1969) for 1-methyl-1-benzoylhydrazine. The following newcompounds have been so prepared:

1-methyl-1-(o-toluyl)hydrazine hydrochloride. M.p. 190°-191° C.

1-methyl-1-(3-chlorobenzoyl)hydrazine. B.p. 130°-140° C./0.05 mm Hg.

We claim:
 1. A process for preparing compounds of formula ##STR54##wherein R may represent: phenyl; phenyl substituted by a radicalselected from (C₁₋₄)alkyl, (C₁₋₄)alkoxy, fluoro, chloro, bromo, nitro,amino, cyano, carbamoyl, carboxy, hydroxymethyl, methylenedioxy andtrifluoromethyl; dichlorophenyl; dimethoxyphenyl; 3.4,5-trimethoxyphenyl;R₂ represents a (C₁₋₄)alkyl group and R₅ stands forhydrogen or chloro, which comprises subjecting to thermal oracid-catalyzed rearrangement a benzoxazine derivative of formula##STR55## wherein R, R₂ and R₅ are as above defined.